Cytoskeletal keratin glycosylation protects epithelial tissue from injury

Nam-on Ku, Diana M. Toivola, Pavel Strnad, M. Bishr Omary

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Keratins 8 and 18 (K8 and K18) are heteropolymeric intermediate filament phosphoglycoproteins of simple-type epithelia. Mutations in K8 and K18 predispose the affected individual to liver disease as they protect hepatocytes from apoptosis. K18 undergoes dynamic O-linked N-acetylglucosamine glycosylation at Ser 30, 31 and 49. We investigated the function of K18 glycosylation by generating mice that overexpress human K18 S30/31/49A substitution mutants that cannot be glycosylated (K18-Gly g-), and compared the susceptibility of these mice to injury with wild-type and other keratin-mutant mice. K18-Gly g- mice are more susceptible to liver and pancreatic injury and apoptosis induced by streptozotocin or to liver injury by combined N-acetyl-D-glucosaminidase inhibition and Fas administration. The enhanced apoptosis in the livers of mice that express K18-Gly- involves the inactivation of Akt1 and protein kinase Cø as a result of their site-specific hypophosphorylation. Akt1 binds to K8, which probably contributes to the reciprocal hyperglycosylation and hypophosphorylation of Akt1 that occurs on K18 hypoglycosylation, and leads to decreased Akt1 kinase activity. Therefore, K18 glycosylation provides a unique protective role in epithelial injury by promoting the phosphorylation and activation of cell-survival kinases.

Original languageEnglish
Pages (from-to)876-885
Number of pages10
JournalNature Cell Biology
Volume12
Issue number9
DOIs
Publication statusPublished - 2010 Sep 1

Fingerprint

Keratins
Glycosylation
Epithelium
Wounds and Injuries
Apoptosis
Liver
Phosphotransferases
K-18 conjugate
Keratin-8
Keratin-18
Hexosaminidases
Acetylglucosamine
Intermediate Filaments
Streptozocin
Protein Kinase C
Liver Diseases
Hepatocytes
Cell Survival
Phosphorylation
Mutation

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Ku, Nam-on ; Toivola, Diana M. ; Strnad, Pavel ; Omary, M. Bishr. / Cytoskeletal keratin glycosylation protects epithelial tissue from injury. In: Nature Cell Biology. 2010 ; Vol. 12, No. 9. pp. 876-885.
@article{4373eb67b80e4f60a6a05a17c7d59179,
title = "Cytoskeletal keratin glycosylation protects epithelial tissue from injury",
abstract = "Keratins 8 and 18 (K8 and K18) are heteropolymeric intermediate filament phosphoglycoproteins of simple-type epithelia. Mutations in K8 and K18 predispose the affected individual to liver disease as they protect hepatocytes from apoptosis. K18 undergoes dynamic O-linked N-acetylglucosamine glycosylation at Ser 30, 31 and 49. We investigated the function of K18 glycosylation by generating mice that overexpress human K18 S30/31/49A substitution mutants that cannot be glycosylated (K18-Gly g-), and compared the susceptibility of these mice to injury with wild-type and other keratin-mutant mice. K18-Gly g- mice are more susceptible to liver and pancreatic injury and apoptosis induced by streptozotocin or to liver injury by combined N-acetyl-D-glucosaminidase inhibition and Fas administration. The enhanced apoptosis in the livers of mice that express K18-Gly- involves the inactivation of Akt1 and protein kinase C{\o} as a result of their site-specific hypophosphorylation. Akt1 binds to K8, which probably contributes to the reciprocal hyperglycosylation and hypophosphorylation of Akt1 that occurs on K18 hypoglycosylation, and leads to decreased Akt1 kinase activity. Therefore, K18 glycosylation provides a unique protective role in epithelial injury by promoting the phosphorylation and activation of cell-survival kinases.",
author = "Nam-on Ku and Toivola, {Diana M.} and Pavel Strnad and Omary, {M. Bishr}",
year = "2010",
month = "9",
day = "1",
doi = "10.1038/ncb2091",
language = "English",
volume = "12",
pages = "876--885",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "9",

}

Cytoskeletal keratin glycosylation protects epithelial tissue from injury. / Ku, Nam-on; Toivola, Diana M.; Strnad, Pavel; Omary, M. Bishr.

In: Nature Cell Biology, Vol. 12, No. 9, 01.09.2010, p. 876-885.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cytoskeletal keratin glycosylation protects epithelial tissue from injury

AU - Ku, Nam-on

AU - Toivola, Diana M.

AU - Strnad, Pavel

AU - Omary, M. Bishr

PY - 2010/9/1

Y1 - 2010/9/1

N2 - Keratins 8 and 18 (K8 and K18) are heteropolymeric intermediate filament phosphoglycoproteins of simple-type epithelia. Mutations in K8 and K18 predispose the affected individual to liver disease as they protect hepatocytes from apoptosis. K18 undergoes dynamic O-linked N-acetylglucosamine glycosylation at Ser 30, 31 and 49. We investigated the function of K18 glycosylation by generating mice that overexpress human K18 S30/31/49A substitution mutants that cannot be glycosylated (K18-Gly g-), and compared the susceptibility of these mice to injury with wild-type and other keratin-mutant mice. K18-Gly g- mice are more susceptible to liver and pancreatic injury and apoptosis induced by streptozotocin or to liver injury by combined N-acetyl-D-glucosaminidase inhibition and Fas administration. The enhanced apoptosis in the livers of mice that express K18-Gly- involves the inactivation of Akt1 and protein kinase Cø as a result of their site-specific hypophosphorylation. Akt1 binds to K8, which probably contributes to the reciprocal hyperglycosylation and hypophosphorylation of Akt1 that occurs on K18 hypoglycosylation, and leads to decreased Akt1 kinase activity. Therefore, K18 glycosylation provides a unique protective role in epithelial injury by promoting the phosphorylation and activation of cell-survival kinases.

AB - Keratins 8 and 18 (K8 and K18) are heteropolymeric intermediate filament phosphoglycoproteins of simple-type epithelia. Mutations in K8 and K18 predispose the affected individual to liver disease as they protect hepatocytes from apoptosis. K18 undergoes dynamic O-linked N-acetylglucosamine glycosylation at Ser 30, 31 and 49. We investigated the function of K18 glycosylation by generating mice that overexpress human K18 S30/31/49A substitution mutants that cannot be glycosylated (K18-Gly g-), and compared the susceptibility of these mice to injury with wild-type and other keratin-mutant mice. K18-Gly g- mice are more susceptible to liver and pancreatic injury and apoptosis induced by streptozotocin or to liver injury by combined N-acetyl-D-glucosaminidase inhibition and Fas administration. The enhanced apoptosis in the livers of mice that express K18-Gly- involves the inactivation of Akt1 and protein kinase Cø as a result of their site-specific hypophosphorylation. Akt1 binds to K8, which probably contributes to the reciprocal hyperglycosylation and hypophosphorylation of Akt1 that occurs on K18 hypoglycosylation, and leads to decreased Akt1 kinase activity. Therefore, K18 glycosylation provides a unique protective role in epithelial injury by promoting the phosphorylation and activation of cell-survival kinases.

UR - http://www.scopus.com/inward/record.url?scp=77956412905&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956412905&partnerID=8YFLogxK

U2 - 10.1038/ncb2091

DO - 10.1038/ncb2091

M3 - Article

VL - 12

SP - 876

EP - 885

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 9

ER -